title: Selective induction of leukemia-associated fusion genes by high-dose ionizing radiation.
abstract: There is strong clinical and epidemiological evidence that ionizing radiation can cause leukemia by inducing DNA damage. This crucial initiation event is believed to be the result of random DNA breakage and misrepair, whereas the subsequent steps, promotion and progression, must rely on mechanisms of selective pressure to provide the expanding leukemic population with its proliferative/renewal advantage. To investigate the susceptibility of human cells to external agents at the genetic recombination stage of leukemogenesis, we subjected two hematopoietic cell lines, KG1 and HL60, to high doses of gamma-irradiation. The irradiation induced the formation of fusion genes characteristic of leukemia in both cell lines, but at a much higher frequency in KG1 than in HL60. In KG1 cells, the AML1-ETO hybrid gene [associated with the t(8;21) translocation of acute myeloid leukemia] occurred significantly more often than the BCR-ABL [associated with t(9;22) chronic myeloid leukemia] or the DEK-CAN [associated with t(6;9) acute myeloid leukemia] fusion genes. These findings support the notion that ionizing radiation can directly generate leukemia-specific fusion genes but emphasize the differing susceptibility of different cell populations and the differing frequency with which the various fusion genes are formed. The selectivity observed at the primary level of gene fusion formation may explain at least in part the differential risk for development of some but not other forms of leukemia after high-dose radiation exposure.
authors.affiliation: Leukaemia Research Fund Centre for Adult Leukaemia, Department of Haematology, Royal Postgraduate Medical School, London, United Kingdom.
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
authors.forename: S
authors.initials: S
authors.lastname: Bose
authors.forename: J
authors.initials: J
authors.lastname: Gora-Tybor
authors.forename: X H
authors.initials: XH
authors.lastname: Yan
authors.forename: J M
authors.initials: JM
authors.lastname: Goldman
authors.forename: J V
authors.initials: JV
authors.lastname: Melo
mesh_terms: D050676:Core Binding Factor Alpha 2 Subunit; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000528:radiation effects; D016044:Fusion Proteins, bcr-abl / Q000032:analysis / Q000235:genetics*; D005720:Gamma Rays; D018922:HL-60 Cells / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D006801:Humans; D007953:Leukemia, Radiation-Induced / Q000235:genetics*; D015513:Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D015514:Oncogene Proteins, Fusion; D016133:Polymerase Chain Reaction; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014178:Translocation, Genetic / Q000528:radiation effects*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C104001:DEK-CAN fusion protein, recombinant; D004273:DNA, Neoplasm; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016044:Fusion Proteins, bcr-abl